Use of alkylphosphocholines in combination with antimetabolites for the treatment of benign and malignant oncoses in humans and mammals

ABSTRACT

The invention relates to the use of alkylphosphocholines in combination with antimetabolites for the treatment of multiple myeloma, colon cancer or renal cancer. Preferred alkylphosphocholines are described by the Formula II. 
     
       
         
         
             
             
         
       
     
     A particularly effective treatment includes administering a combination of perifosine and capecitabine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part (CIP) of U.S. patent application Ser. No. 10/632,187, filed on Jul. 30, 2003, which claims the benefit of U.S. Provisional Application No. 60/399,615, filed Jul. 30, 2002, which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Alkylphosphocholines are a new class of organic compounds, which exhibit diversified anti-neoplastic activities (M. Lohmeyer and R. Bittman, Antitumor Ether Lipids and Alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)). The effect of the alkylphosphocholines in this connection may be based on different, molecular and biochemical mechanisms, some of which take place on the level of the plasma membrane of the cell.

It is well known that alkylphosphocholines influence inositol metabolism, the interaction with phospholipases or inhibition of protein kinase C and thus that this class of substances has a general influence on cellular signal transduction (K. Maly et al., Interference of New Alkylphospholipid Analogues With Mitogenic Signal Transduction, Anti-Cancer Drug Design, 10, 411-425 (1995); and P. Hilgard, et al., D21266, A New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur. J. Cancer, 33 (3), 442-446 (1997)). Thus, the alkylphosphocholine perifosine shows growth-inhibitory properties in relation to various melanoma, CNS, lung, colon, prostate and breast cancer cell lines with an IC₅₀ ranging from 0.2 to 20 μM.

It is further known that perifosine blocks tumor cells in the G₁-S and G₂-M phase of the cell cycle (V. Patel, et al., A Novel Alkylphospholipid, Induces p. 21 ^(Waf1) Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclindependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62, 1401-1409 (2002)).

It is known that the use of alkylphosphocholines before or together with radiation therapy leads its synergistic effects during the treatment of tumors (P. Principe et al., Evaluation of Combinations of Antineoplastic Ether Phospholipids and Chemotherapeutic Drugs, Anti-Cancer Drugs, 3 (6), 577-587 (1992)). It has also been reported that different glycerol-3-phospholipids, such as ET-18-OOCH₃, in combination with different DNA-interacting substances or tubulin binders increase the anti-tumor activity in vitro in a different tumor cell lines (P. Principe et al., Synergistic Cytotoxic Effect of Aza-alkylphospholipids in Association with Chemotherapeutic Drugs, J. Lipid Mediators Cell Signalling, 10 (1-2), 171-173 (1994)).

Despite advances in the treatment of cancer using perifosine and a variety of other antitumor agents, there still exists a need in developing more effective therapies for the treatment of a variety of different types of cancer. Certain types of cancers, such as multiple myeloma, renal cancer, breast cancer and colon cancer have proved to be particularly difficult to control. Thus, an effective means of treating these cancers that prolong the survival rate of patients without causing serious side effects would be a considerable advance.

BRIEF SUMMARY OF THE INVENTION

Surprisingly, it has been found that administering specific combinations of an alkylphosphocholine and an antimetabolite show a synergistic effect towards the treatment of multiple myeloma, breast cancer, colon cancer and renal cancer. The combination therapy allows for the use of lower doses of the individual antitumor agents and thus is less toxic to the patient.

One aspect of the present invention involves a method of treating multiple myeloma, colon, breast or renal cancer using a combination of an alkylphosphocholine and an antimetabolite.

Another aspect of the present invent involves a method of treating multiple myeloma, breast, colon or renal cancer comprising administering a therapeutically effective amount of perifosine or miltefosine and a therapeutically effective amount of an antimetabolite.

Still another aspect of the present invention involves a method of treating multiple myeloma, colon, breast or renal cancer comprising administering a therapeutically effective amount of perifosine and a therapeutically amount of capecitabine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel use of linear alkylphosphocholines of the general Formulas I and II in an inventive combination with other medicinal drugs for the treatment of multiple myeloma, renal cancer or colon cancer. According to one aspect of the invention, the compounds of the general Formulas I and II can be used in an inventive combination with an antimetabolite. The alkylphosphocholines of the general Formulas I and II, on which the invention is based, may be used in the form of finished medicinal drugs. The compounds, on which the invention is based, are described by the general Formulas I and II:

in which, independently of one another,

-   n, m, p, z is a whole number between 0 and 4, -   X is O, S, NH; -   R is hydrogen, a linear or branched C₁ to C₂₀ alkyl group, which may     be saturated or unsaturated with one to three double and/or triple     bonds and unsubstituted or optionally substituted at the same or at     different carbon atoms with one, two or more halogen, nitro, cyano,     hydroxy, C₁ to C₆ alkoxy, amino, mono-(C₁ to C₄) alkylamino or     di-(C₁ to C₄) alkylamino groups, -   R₁, R₂, R₃ independently of one another represent hydrogen, a linear     or branched (C_(I) to C₆) alkyl group, preferably methyl and ethyl,     a (C₃ to CO cyclo alkyl group, which may be unsubstituted or     optionally substituted at the same or different carbon atoms with     one, two or more halogen, nitro, cyano, hydroxy, C₁ to C₆ alkoxy,     amino, mono-(C₁ to C₄) alkylamino or di-(C₁ to C₄) alkylamino     groups.

As used herein, multiple myeloma refers to cancer of the white blood cells (or plasma). As used herein, breast cancer refers to any cancer originating in the breast tissue including carcinomas and adenocarcinomas. As used herein colon cancer refers to any cancer originating in the colon, including all types of colon and colorectal adenocarcinoma and carcinoma. As used herein, renal cancer refers to any cancer that originates in the kidney, including, but not limited to, renal cell carcinoma, renal cell adenocarcinoma, clear cell carcinoma, renal pelvis carcinoma, squamous cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma, Wilms' tumor, and mixed epithelial stromal tumor.

According to one aspect of the invention, a method for controlling multiple myeloma, renal cancer, breast cancer or colon cancer in humans and in mammals is provided and comprises administering at least one of the compounds of the general Formula I and II on which the invention is based to the human or a mammal in an amount effective for tumor treatment before or during a treatment with an antimetabolite.

The therapeutically effective dose, to be administered for the treatment, of the particular compound of the general formula I and II on which the invention is based depends inter alia on the nature and the stage of the oncosis, the age and sex of the patient, the mode of administration and the duration of treatment. The compounds on which the invention are based can be administered in a drug product as liquid, semisolid and solid drug forms. This takes place in the manner suitable in each case in the form of aerosols, oral powders, dusting powders and epipastics, uncoated tablets, coated tablets, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, pastilles, capsules or suppositories.

In one embodiment, the present invention provides a method of treating multiple myeloma, renal cancer, breast cancer or colon cancer by administering an alkylphosphocholine of the Formulas I or II before and/or during administration of at least one antimetabolite. Preferred alkylphosphocholines used in accordance with the present invention include perifosine (octadecyl 1,1-dimethylpiperidinium-4-yl phosphate) and miltefosine. A particularly preferred alkylphosphocholines is perifosine. Preferred antimetabolites include but are not limited to 5-azacytidine, 2-mercaptopurine, 5-fluorouracil, 6-thioguanine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, doxifluridine, floxuridine, fludarabine, forodesine, gemcitabine, nelarabine, pentostatin, sapacitabine, thiarabine or Troxacitabine. A particularly preferred antimetabolite is capecitabine.

In one preferred embodiment, a therapeutically effective amount of perifosine in combination with a therapeutically effective amount of 5-flurouracil or a prodrug of 5-flurouracil is administered to a patient with multiple myeloma, colon cancer or renal cancer. A preferred prodrug of 5-flurouracil is capecitabine. The amount of perifosine may range from about 20 mg/day to about 100 mg/day. The amount of capecitabine may range from about 500 mg/m² to about 2500 mg/m² daily.

In another preferred embodiment, a therapeutically effective amount of miltefosine in combination with a therapeutically effective amount of 5-flurouracil or a prodrug of 5-flurouracil is administered to a patient with multiple myeloma, colon cancer or renal cancer. A preferred prodrug of 5-flurouracil is capecitabine. The amount of miltefosine may range from about 20 mg/day to about 100 mg/day. The amount of capecitabine may range from about 500 mg/m² to about 2500 mg/m² daily. 

1. A method of treating cancer, wherein the method comprises administering a therapeutically effective amount of an alkylphosphocholine compound of the general Formula I or II:

in which, independently of one another: m, n, p, z are a whole number between 0 and 4; X is O, S, NH; R is hydrogen, a linear or branched C₁ to C₂₀ alkyl group, which may be saturated or unsaturated with one to three double and/or triple bonds and unsubstituted or optionally substituted at the same or at different carbon atoms with one, two or more halogen, nitro, cyano, hydroxy, C₁ to C₆ alkoxy, amino, mono-(C₁ to C₄)-alkylamino or di-(C₁ to C₄)-alkylamino groups; R₁, R₂, R₃ independently of one another represent hydrogen, a linear or branched (C₁ to C₆) alkyl group, preferably methyl and ethyl, a (C₃ to C₇) cycloalkyl group, which may be unsubstituted or optionally substituted at the same or different carbon atoms with one, two or more halogen, nitro, cyano, hydroxy, (C₁ to C₆) alkoxy, amino, mono-(C₁ to C₄) alkylamino or di-(C₁ to C₄) alkylamino groups and pharmaceutically acceptable salts and prodrugs thereof, wherein said alkylphosphocholine is administered before and/or during treatment with at least one antimetabolite.
 2. A method of treating cancer, wherein the method comprises administering a therapeutically effective amount of an alkylphosphocholine compound having the structure of Formula I:

in which, independently of one another: m, n are a whole number between 0 and 4; X is O; R is H or a straight-chain or branched (C₁-C₁₇)-alkyl group which may be saturated or unsaturated with one to three double and/or triple bonds; R₁, R₂, R₃ are, independently of one another, H or a straight-chain or branched (C₁-C₆)-alkyl group, preferably methyl and ethyl, a (C₃-C₇)-cycloalkyl group, wherein said alkylphosphocholine is administered before and/or during treatment with at least one antimetabolite.
 3. A method of treating cancer, wherein the method comprises administering a therapeutically effective amount of an alkylphosphocholine compound having the structure of Formula II:

in which, independently of one another: m, n, p, z are a whole number between 0 and 4; X is O; R is H, a straight-chain or branched (C₁-C₁₇)-alkyl group which may be saturated or unsaturated with one or two double and/or triple bonds; R₁, R₂ are, independently of one another, H or a straight-chain or branched (C₁-C₆)-alkyl group, preferably methyl and ethyl, a (C₃-C₇)-cycloalkyl group, wherein said alkylphosphocholine is administered before and/or during treatment with at least one antimetabolite.
 4. The method according to claim 1, wherein said alkylphosphocholine is octadecyl 1,1-dimethylpiperidinium-4-yl phosphate (perifosine).
 5. The method according to claim 1, wherein said method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an alkylphosphocholine compound of the general Formula I or II, customary pharmaceutical carriers, excipients and/or diluents, and wherein said composition is administered before and/or during the treatment with at least one antimetabolite.
 6. The method according to claim 1, wherein said alkylphosphocholine is administered before and/or during treatment with two or more antimetabolites.
 7. The method according to claim 1, wherein said antimetabolite is selected from the group consisting of 5-Azacytidine, 2-Mercaptopurine, 5-Fluorouracyl, 6-Thioguanine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Decitabine, Doxifluridine, Floxuridine, Fludarabine, Forodesine, Gemcitabine, Nelarabine, Pentostatin, Sapacitabine, Thiarabine and Troxacitabine.
 8. The method according to claim 1, wherein said cancer is selected from the group consisting of multiple myeloma, colon cancer, and renal cancer.
 9. The method according to claim 1, wherein said cancer is selected from the group consisting of multiple myeloma, colon cancer, and renal cancer, and wherein said alkylphosphocholine is octadecyl 1,1-dimethylpiperidinium-4-yl phosphate (perifosine), and wherein said antimetabolite is selected from the group consisting of 5-Azacytidine, 2-Mercaptopurine, 5-Fluorouracyl, 6-Thioguanine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Decitabine, Doxifluridine, Floxuridine, Fludarabine, Forodesine, Gemcitabine, Nelarabine, Pentostatin, Sapacitabine, Thiarabine and Troxacitabine.
 10. The method according to claim 9, wherein said antimetabolite is capecitibine.
 11. The method according to claim 9, wherein said cancer is colon cancer, and wherein said antimetabolite is capecitibine.
 12. A pharmaceutical composition comprising at least one alkylphosphocholine of the general Formula I or II according to claim 1 and, optionally carriers and/or excipients, for use in the treatment of cancer, before and/or during the treatment with at least one antimetabolite.
 13. The pharmaceutical composition according to claim 12, wherein the antimetabolite is selected from the group consisting of 5-Azacytidine, 2-Mercaptopurine, 5-Fluorouracyl, 6-Thioguanine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Decitabine, Doxifluridine, Floxuridine, Fludarabine, Forodesine, Gemcitabine, Nelarabine, Pentostatin, Sapacitabine, Thiarabine and Troxacitabine.
 14. The pharmaceutical composition according to claim 12, wherein said alkylphosphocholine is octadecyl 1,1-dimethylpiperidinium-4-yl phosphate.
 15. The pharmaceutical composition according to claim 12, wherein said cancer is selected from the group consisting of multiple myeloma, colon cancer, renal cancer. 